ClinVar Miner

Submissions for variant NM_002693.2(POLG):c.1402A>G (p.Asn468Asp) (rs145843073)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658725 SCV000242282 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing A variant of unknown significance has been identified in the POLG gene. The N468D missense substitution was reported in three members of a family with progressive external ophthalmoplegia (PEO), peripheral neuropathy, and parkinsonism; these individuals were also heterozygous for another POLG variant on the other allele, suggesting autosomal recessive inheritance of PEO in this family. Based on the available information, the authors could not conclusively determine whether N468D was related to the phenotype in the affected family members (Luoma et al., 2004, Palin et al., 2013). N468D was subsequently identified in two unrelated families with PEO, cerebellar ataxia, or other neurological symptoms suggestive of a mitochondrial disorder; but affected individuals did not have a second POLG variant on the other allele (Schulte et al., 2009; Blok et al., 2009). The N468D variant is observed in 6/6614 (0.1%) alleles from individuals of Finnish background (Lek et al., 2016). The N468D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This variant is predicted to be within the linker region of the protein, where many missense pathogenic variants have been reported in association withPOLG-related disorders (Human DNA Polymerase Gamma Mutation Database). However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the N468D variant is damaging to the protein structure/function. Based on the available evidence, it is currently unclear whetherthis variant is a disease-associated pathogenic variant causing autosomal recessive and/or dominant PEO, or whetherit is a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000658725 SCV000331575 uncertain significance not provided 2018-04-17 criteria provided, single submitter clinical testing
Invitae RCV000470781 SCV000543881 uncertain significance Progressive sclerosing poliodystrophy 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 468 of the POLG protein (p.Asn468Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs145843073, ExAC 0.09%). This variant has been reported in individuals affected with progressive external ophthalmoplegia with or without parkinsonism, mitochondrial neurogastrointestinal encephalopathy syndrome, and/or tetraparesis (PMID: 15351195, 22647225, 16401742). It has also been reported in several additional individuals with POLG-related disorders, but a second variant in POLG was not identified in these individuals (PMID: 19578034, 21880868). ClinVar contains an entry for this variant (Variation ID: 206596). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000658725 SCV000614702 uncertain significance not provided 2020-05-27 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658725 SCV000780512 uncertain significance not provided 2020-04-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000717211 SCV000848060 uncertain significance Seizures 2018-05-02 criteria provided, single submitter clinical testing The p.N468D variant (also known as c.1402A>G), located in coding exon 6 of the POLG gene, results from an A to G substitution at nucleotide position 1402. The asparagine at codon 468 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been detected as both heterozygous and compound heterozygous in several individuals with a variety of phenotypes including external ophthalmoplegia, parkinsonism, cerebellar ataxia, sensory neuropathy, and MNGIE syndrome. In addition, this alteration was detected in several unaffected family members and was absent in an affected relative of heterozygous carriers (Luoma P et al. Lancet;364:875-82; Woodbridge P et al. Intern Med J, 2013 Feb;43:150-6; Blok MJ et al. J. Med. Genet., 2009 Nov;46:776-85; Schulte C et al. Neurology, 2009 Sep;73:898-900; Wanrooij S et al. Nucleic Acids Res., 2004 Jun;32:3053-64). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.​ Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine RCV000470781 SCV000886902 pathogenic Progressive sclerosing poliodystrophy 2018-10-01 criteria provided, single submitter clinical testing The NM_002693.2:c.1402A>G (NP_002684.1:p.Asn468Asp) [GRCH38: NC_000015.10:g.89327198T>C] variant in POLG gene is interpretated to be a Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported in PMID:15351195 ; 16401742 . This variant meets the following evidence codes reported in the ACMG-guideline. PS4:Prevalence of variant in affecteds statistically increased over controls. PS1:This variation causes same amino-acid change as an established pathogenic variant. PS3:Well established functional studies show a deleterious effect on POLG. Based on the evidence criteria codes applied, the variant is suggested to be Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000763995 SCV000894946 uncertain significance Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 1 (MNGIE type); Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2018-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001610504 SCV001156973 uncertain significance Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1 2021-09-01 criteria provided, single submitter clinical testing The POLG c.1402A>G; p.Asn468Asp variant is reported in the literature in individuals affected with autosomal recessive progressive external ophthalmoplegia (Luoma 2004, Palin 2013, Woodbridge 2013). The affected individuals identified in these reports were compound heterozygous for the p.Asn468Asp variant while heterozygous carriers in the same family were unaffected. The variant has also been shown to co-segregate with disease in families with autosomal recessive progressive external ophthalmoplegia (Wanrooij 2004). This variant is reported with conflicting interpretations in ClinVar (Variation ID: 206596). Another variant in this region, p.Ala467Thr, is considered the most common pathogenic POLG variant (Variation ID: 13496). However, due to limited functional evidence, the clinical significance of the p.Asn468Asp variant is uncertain.
Baylor Genetics RCV001004603 SCV001163773 likely pathogenic Progressive sclerosing poliodystrophy; Mitochondrial DNA depletion syndrome 4B, MNGIE type criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001027840 SCV001190460 uncertain significance Progressive sclerosing poliodystrophy; Autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions 1; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1; Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; Mitochondrial DNA depletion syndrome 4B, MNGIE type 2019-03-12 criteria provided, single submitter clinical testing POLG NM_002693.2 exon 7 p.Asn468Asp (c.1402A>G): This variant has been reported in the literature in the compound heterozygous state in at least 3 individuals with autosomal recessive progressive external opthalmoplegia in addition to ataxia, tetraparesis, and/or parkinsonism, segregating with disease in two affected family members (Luoma 2004 PMID:15351195, Gonzalez-Viogue 2006 PMID:16401742, Woodbridge 2013 PMID:22647225). This variant has also been identified in multiple individuals with suspected POLG-deficiency who did not have a second identifiable variant in the POLG gene (Blok 2009 PMID:19578034, Tang 2011 PMID:21880868). This variant is present in 0.07% (18/25122) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-89870429-T-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar (Variation ID:206596). This variant amino acid Aspartic Acid (Asp) is present in several species including two mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Illumina Clinical Services Laboratory,Illumina RCV001117972 SCV001276218 uncertain significance POLG-Related Spectrum Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
New York Genome Center RCV001263305 SCV001441346 uncertain significance Seizures; Intellectual disability 2020-04-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV001330959 SCV001522834 likely pathogenic Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 2020-11-04 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000658725 SCV001716240 uncertain significance not provided 2020-12-29 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678827 SCV000805013 uncertain significance Lennox-Gastaut syndrome 2016-12-05 no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000658725 SCV001952043 pathogenic not provided no assertion criteria provided clinical testing

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